In the past PPG term, we have unequivocally linked the genes causing early onset Alzheimer's disease (AD) directly to functions'within endocytic and autophagic pathways of the lysosomal system, documenting specific impairment of these functions beginning at the earliest stages of AD. We propose to validate further our novel conceptual framework that positions the lysosomal system as a common primary target for disruption by diverse genetic and environmental AD-risk factors. Preliminary data support the working hypothesis that cumulative "hits" to multiple sites within the endocytic and autophagy pathways in AD cause selective failures of vesicular retrograde transport and signaling, impaired clearance of pathogenic proteins including AP, neurotic dystrophy, and neurodegeneration. The four Projects apply a tightly integrated multidisciplinary approach to study the highly dynamic interplay among lysosome pathway compartments. Individual Projects focus mainly on distinct facets of the entire lysosomal system - the biological and genetic regulation of early endosome signaling (Projects 1, 4 respectively), late endosome/exosome biology (Project 3), and autophagy/lysosome function (Project 2) - thus enabling us to define comprehensively how specific major AD-risk factors disrupt the lysosomal system with significant pathogenic consequences. Innovative technologies from single-neuron gene profiling to video microscopy and high voltage immunogold EM imaging will be applied to patient cells and our novel mouse models. In addition to defining the mechanisms underlying pathobiology induced by key AD-risk factors (APP, cholesterol, presenilin, cystatin C, neurotrophin deprivation), we will provide the rationale and validation for innovative therapeutic approaches to AD, including modulators of endocytosis and lipid-mediated AD pathologies (Project 1), autophagy/lysosomal remediation (Project 2), exosome-based modulation and cystatin C-based therapies (Project 3), and drug target identification within APP/neurotrophin signaling pathways promoting neuron survival (Project 4). Validation for one or more of these new approaches will have significant impact on realizing therapeutics for AD and other major aging-related neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Addressing an urgent need for additional perspectives on effective therapies for Alzheimer's Disease, our Program advances a novel biological framework for understanding how AD develops and that identifies new directions for the therapy of AD and possibly other aging-related diseases. Exploiting this framework, we propose to validate multiple innovative therapeutic approaches for AD. REVIEW OF INDIVUDUAL COMPONENTS CORE A: ADMINISTRATIVE CORE;Dr. Ralph A. Nixon, Core Leader (CL) DESCRIPTION (provided by applicant): Core A will facilitate the research aims of all projects and cores by providing all necessary administrative support, by fostering collaborative interactions and cross-fertilization of ideas across projects/cores, by facilitating education/training, and recruitment activities, and by providing for internal and external scientific review of the research. To achieve these objectives, the core will: 1) Monitor fiscal activities of the projects and cores, and centralize the administration of clerical and personnel matters. 2) Facilitate communication among investigators within the Program by holding monthly meetings to discuss progress made in each Program component. Communication and quality control will also be enhanced by a system of internal review of research findings prepared for progress reports and manuscripts. 3) Enhance ongoing scientific education and training of Program investigations through a range of seminar series, each involving a multidisciplinary selection of New York area and national/international speakers from the Alzheimer's disease research fields, the neurosciences, and neuroimaging, respectively. 4) Provide for ongoing scientific review of accomplishments, activities, and future directions of this Program Project by an External Advisory Committee of scientific experts. 5) Provide statistical consultation and develop new statistical methodologies as necessary. 6) Identify, recruit and mentor new investigators and trainees whose research can contribute to the long-range aims of this Program Project. Facilitate the use of resources generated through this Program by other investigators. PUBLIC HEALTH RELEVANCE: This Core supplies essentials support for our Program, which advances a novel biological framework for understanding how Alzheimer's disease develops and which identifies new directions for the therapy of AD and possibly other aging-related diseases.